This invention relates to isotope-labeled compounds of rapamycin 42-ester with 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid (CCI-779).
CCI-779 is a derivative of rapamycin, which is a macrocyclic triene antibiotic produced naturally by Streptomyces hygroscopicus. The preparation and use of CCI-779 is described in U.S. Pat. No. 5,362,718. Regioselective syntheses of CCI-779 are described in U.S. Pat. No. 6,277,983 and US Patent Publication No. 2005/0033046 A1.
Rapamycin has been found useful in an array of applications based on its antitumoral and immunosuppressive effects. Such uses include preventing, inhibiting, or treating transplant rejection, graft vs. host disease, autoimmune diseases including systemic lupus erythematosis, inflammatory diseases including pulmonary and ocular inflammation, adult T cell leukemia/lymphoma, solid tumors, fungal infections, and hyperproliferative vascular disorders, including smooth muscle cell proliferation and intimal thickening following vascular surgery. Rapamycin and rapamycin derivatives, including CCI-779, continue to be studied for treatment of these and other conditions.
Both radio- and stable-isotope-labeled CCI-779 are required for drug absorption, distribution, metabolism and excretion (ADME) studies and as standard for quantitative mass spectrometry (MS) bio-analytical studies. Clinically useful isotope-labeled CCI-779, either stable-isotope-labeled (e.g., deuterium, 13C) or radioactive-isotope-labeled (e.g., tritium, 14C), has been made through labeling its 3-hydroxy-2-(hydroxymethyl)-2-methylpropionic acid side chain. However, this ester-linked side chain has been found unsuitable for labeling due to metabolic instability. Similarly, the 7-methoxy moiety in the rapamycin skeleton is unsuitable for labeling (US Patent Publication No. 2004/0198762 A1).
Accordingly, what is needed are CCI-779 compounds isotope-labeled in metabolically resistant sites having increased metabolic stability and processes for their preparation.